PROJECT SUMMARY/ABSTRACT Hippocampal atrophy is associated with memory impairment as well as conversion from cognitively normal status and mild cognitive impairment to Alzheimer's disease (AD) making it a potential target for AD preventive strategies. Physical activity is a promising candidate in the prevention of AD because of its beneficial effects on hippocampal atrophy. It has been shown to slow or perhaps even reverse hippocampal atrophy, but how this occurs is not yet completely understood. The proposed study aims to address whether physical activity exerts beneficial effects on hippocampal atrophy through angio- and neurogenesis pathways. In Aim 1, we will evaluate the effect of physical activity on pathways of neurogenesis (using brain-derived neurotrophic factor (BDNF) as a marker) and angiogenesis (using vascular endothelial growth factor (VEGF) as a marker). We hypothesize that physical activity acts as a promoter of these pathways. In Aim 2, we will characterize the relationship of BDNF and VEGF with neuroimaging markers. We have 7T markers of both hippocampal subfield volumes and small vessel density. We hypothesize that BDNF/VEGF pathways partially explain the relationship between physical activity and hippocampal subfield volume and small vessel density. Accordingly, in Aim 3 we will examine whether BDNF and VEGF explain these relationships. This proposed research project leverages existing data obtained from two independently funded studies, but it does not overlap with their scope of work: 1) the main Lifestyle Interventions and Independence for Elders (LIFE) Study evaluating a physical activity intervention compared to a health education control to prevent mobility disability (PI: Pahor); and 2) a neuroimaging sub-study evaluating the effect of physical activity on hippocampal volume and small vessel density (PIs: Rosano and Aizenstein). I have already obtained initial funding to measure peripheral levels of BDNF and VEGF as well as inflammatory cytokines (funds obtained from the University of Pittsburgh Claude D. Pepper Center). The LIFE study allows us to evaluate these relationships among older, frailer adults than those typically included in randomized controlled trials. This study will provide novel information on effect sizes of changes in BDNF and VEGF, as well as other peripheral factors, in response to moderate intensity physical activity in very old adults, and it will elucidate their role in hippocampal atrophy. This information is critical to plan intervention studies to modify BDNF and VEGF levels and to potentiate the neuroprotective effects of physical activity. Through the proposed research project and carefully designed training plan I will attain my three main training goals: 1) Apply advanced skills in neuroepidemiological research methods, 2) Gain translational research experience, and 3) Obtain professional development skills. This work will equip me to carry out future studies as an independent investigator with expertise in promotion of neurovascular integrity to preserve cognitive function.